Affordable Access

Access to the full text

RARalpha-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia.

Authors
  • Guidez, Fabien
  • Parks, Sarah
  • Wong, Henna
  • Jovanovic, Jelena V
  • Mays, Ashley
  • Gilkes, Amanda F
  • Mills, Kenneth I
  • Guillemin, Marie-Claude
  • Hobbs, Robin M
  • Pandolfi, Pier Paolo
  • de Thé, Hugues
  • Solomon, Ellen
  • Grimwade, David
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Publication Date
Nov 13, 2007
Volume
104
Issue
47
Pages
18694–18699
Identifiers
DOI: 10.1073/pnas.0704433104
PMID: 18000064
PMCID: PMC2141839
Source
USPC - SET - SVS
License
Green

Abstract

Leukemia-associated chimeric oncoproteins often act as transcriptional repressors, targeting promoters of master genes involved in hematopoiesis. We show that CRABPI (encoding cellular retinoic acid binding protein I) is a target of PLZF, which is fused to RARalpha by the t(11;17)(q23;q21) translocation associated with retinoic acid (RA)-resistant acute promyelocytic leukemia (APL). PLZF represses the CRABPI locus through propagation of chromatin condensation from a remote intronic binding element culminating in silencing of the promoter. Although the canonical, PLZF-RARalpha oncoprotein has no impact on PLZF-mediated repression, the reciprocal translocation product RARalpha-PLZF binds to this remote binding site, recruiting p300, inducing promoter hypomethylation and CRABPI gene up-regulation. In line with these observations, RA-resistant murine PLZF/RARalpha+RARalpha/PLZF APL blasts express much higher levels of CRABPI than standard RA-sensitive PML/RARalpha APL. RARalpha-PLZF confers RA resistance to a retinoid-sensitive acute myeloid leukemia (AML) cell line in a CRABPI-dependent fashion. This study supports an active role for PLZF and RARalpha-PLZF in leukemogenesis, identifies up-regulation of CRABPI as a mechanism contributing to retinoid resistance, and reveals the ability of the reciprocal fusion gene products to mediate distinct epigenetic effects contributing to the leukemic phenotype.

Report this publication

Statistics

Seen <100 times